Glass-ionomer cements containing amino acids

ABSTRACT

Disclosed are ionomeric compositions and ionomeric cements containing the compositions. The cements are useful in dental and orthopedic medicine.

BACKGROUND OF THE INVENTION

Glass-ionomer cements were first developed about thirty years ago [1].Glass-ionomer cements typically contain an ionic polymer compositionsuch as an acrylic acid homo- or co-polymer, and a reactive glasscomposition such as a calcium fluoride-alumino-silicate glass powder.The ionic polymer is provided in aqueous liquid form, and the reactiveglass is provided in powdery form. When these two compositions are mixedin water, a cement setting reaction takes place. These cements are knownfor their unique properties such as direct adhesion to tooth structureand base metal [2, 3], anticariogenic properties due to release offluoride [4], thermal compatibility with tooth enamel and dentin becauseof low coefficients of thermal expansion similar to those of toothstructure [5], minimized microleakage at the tooth-enamel interface dueto low shrinkage [6], biological compatibility and low cytotoxicity[7,8]. An acid-base interaction plays a major role in conventionalglass-ionomer cements or self-cured cements [9, 10]. A similarinteraction occurs when the cement contacts tooth enamel or dentin,which mainly contains hydroxyapatite (Ca²⁺ and PO⁴⁻), and Type Icollagen [6, 11]. Salt bridge formation is an essential aspect to theadhesion. Due to the salt bridges that form between the cement and toothsurfaces, these cements have been particularly useful as dentaladhesives and anterior tooth restoratives [9].

Like enamel and dentin, bone also contains hydroxyapatite and Type Icollagen [6, 11]. Based on the compositions, bone is very similar todentin [6]. This is the basis for using glass-ionomer cements for boneadhesives and repair applications. Conventional bone cements areacrylate cements that provide fixation of a prosthesis through aso-called “mechanical interlock” between the acrylate resins and porousbone structures [12]. Unlike conventional bone cements, theglass-ionomer cements adhere to bone by means of formation of ionicbonding or salt-bridges. If hybrid systems (containing vinyl andcarboxylic acid functionalities) are introduced, in situ polymerizationoccurs through both groups and dual-curing cements form. As a result,the salt bridges and the mechanical interlocks together play animportant role in strengthening the interfacial bonding [6, 11, 13].

Conventional glass-ionomer cements have been used as bone cements[14-16]. Two glass-ionomer-type bone cements are manufactured inGermany, one called IONOS, and the other called Ionocerm. They aretwo-component systems, in which one component is composed of a copolymerof acrylic and maleic acid in aqueous solution and the second is acalcium-aluminum-fluoro-silicate glass [14-15]. These formulations aresimilar to the dental glass-ionomer cements manufactured by ESPE DentalCo. (Germany)[17]. One preliminary study on otological surgery showedthat these cements were very promising in terms of both adhesion andbiocompatibility [14]. Another study showed that they proved valuable intranslabyrinthine acoustic neuroma surgery in that that the cements wereeasy to use, and did not cause observable side effects [15]. Negativeresults related to lower bonding strengths have been reported, however,[16]. Literature reporting further developments in orthopaedicapplications of glass-ionomer cements is sparse, however.

Commercial dental conventional glass-ionomer cement systems, such aspoly(acrylic acid) or poly(acrylic acid-co-itaconic acid), haveshortcomings. Problems associated with brittleness and low tensile andflexural strengths have limited use of the current conventionalglass-ionomer cements to certain low stress-bearing sites such as ClassIII and Class V cavities. Two major problems regarding the polymermatrix are believed to exist. One problem resides in the direct or veryclose attachment or proximity of all the carboxylic acid (COOH) groupsto the polymer backbone. Not all the carboxyl groups of polyacids areconverted to carboxylate groups during the course of the reaction andutilized in salt-bridge formations [18, 19]. Some free COOH groupsremain unreacted because they are inaccessible due to steric hindrance.Also, when the polyacrylate chain is largely ionized, the remaininghydrogen becomes firmly bound by electrostatic forces. As a result, themetal ions are increasingly hindered in their movement and capability toreact at carboxyl sites. The speculation is that the strength andfracture resistance of the material are weakened due to this sterichindrance, which brings about significantly reduced interactions betweenaluminum cations (Al++) and carboxylate anions (COO—) (and thus lesscluster or salt bridge formation) in the cement.

The second problem deals with molecular weight. It is well-known thatmechanical strengths are very much dependent upon molecular weight,except for those primary chemical interactions [20]. Increase inmolecular weight enhances the mechanical performance of the materials[21]. The molecular weight of highly ordered poly(acrylic acid) and itscopolymers are severely limited by a polyelectrolyte effect.Introduction of monomers with various spacer lengths for the carboxylicacid may serve to increase the molecular weight of these polymers. U.S.Pat. No. 5,369,142 to Culbertson and Kao, and Kao et al., Dent. Mater12: 44-51 (1996), teach ionomeric glass cement compositions wherein thecopolymer is modified to include an amino acid e.g., N-acryloylsubstituted amino acid. Kao found increases in diametral tensile,compressive and/or flexural strengths and fracture toughness in cementsin which the co-polymer contained an amino acid.

Despite these improvements, however, there remains a need fororthopaedic and dental cements that are stronger and exhibit greaterworking time in which to allow dental practitioners and orthopaedicsurgeons to work with them.

SUMMARY OF THE INVENTION

One aspect of the present invention is directed to a composition formaking an ionomeric cement. The composition contains at least onecopolymer containing at least two different carboxylic acid-containingmonomers, wherein the copolymer has pendent polymerizable functionalgroups, and a comonomer containing one or more functional groupsreactive with the polymerizable functional groups. The comonomer, atleast one of the carboxylic acid containing monomers, or both, containsan amino acid moiety. In preferred embodiments, the copolymer containsthree carboxylic acid monomers, two of which are acrylic acid anditaconic acid, and the third monomer is an acryloyl- or methacryloylderivative of beta-alanine, glycine, aspartic acid, glutamic acid,6-aminocaproic acid or methionine.

Another aspect of the present invention is directed to an ionomericcement composition. The cement composition contains, in addition to thecopolymer and comonomer, a reactive filler and water.

A further aspect of the present invention is directed to apolymerization system, per se. The system contains at least onecopolymer containing at least two different carboxylic acid-containingmonomers, wherein the copolymer has pendent polymerizable functionalgroups, and a comonomer containing one or more groups reactive with thepolymerizable functional group. At least one of the monomers, thecomonomer or both contains an amino acid moiety.

Yet another aspect of the present invention is directed to a kit thatcontains at least one package containing various of the ingredientsnecessary to prepare the ionomeric cement compositions. In preferredembodiments wherein the cement is ultimately prepared using a redoxpolymerization initiation system, one package contains the reactivefiller and the reducing agent (preferably in microencapsulated form),and another package contains the copolymer, comonomer, oxidizing agentand water. In other embodiments a first package contains the reactivefiller, copolymer and comonomer, and the second package contains water.If a redox system is used, the first package may also contain thereducing agent and the second package may contain the oxidizing agent.The reducing agent and the oxidizing agent may be in either package.Methods of making and using the cements are also provided.

Ionomeric cement compositions of the present invention arenon-biodegradable; they form a rigid hydro-gel that can be loaded withbioactive agents for release over extended periods of time. They exhibitsuperior biocompatibility, hydrophilicity, reduced cytotoxicity; verylow polymerization shrinkage and exotherm; self-healing characteristicsin that ionic cross-links that break due to mechanical forces may reformover time; and they exhibit longer working time and stronger and moredurable chemical bonding to bone and metal alloys.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a flow diagram of a “one-pot” synthesis of a terpolymergrafted with isocyanatoethyl methacrylate (IEM), according to thepresent invention.

FIG. 2 is a bar graph illustrating compressive strengths of ionomericcements of the present invention having pendent vinyl groups from IEMgraft and polymerized via photo-initiation.

FIG. 3 is a bar graph illustrating flexural and diametral tensilestrengths of ionomeric cements of the present invention having pendentvinyl groups from IEM graft and polymerized via photo-initiation.

FIG. 4 is a bar graph illustrating compressive and diametral tensilestrengths of ionomeric cements of the present invention having pendentvinyl groups from IEM graft and polymerized via redox-initiation.

FIG. 5 is a bar graph illustrating flexural and diametral tensilestrengths of ionomeric cements of the present invention having pendentvinyl groups obtained through glycydol methacrylate (GM) grafting andpolymerized via redox-initiation.

FIG. 6 is a bar graph illustrating compressive strengths and viscositiesof ionomeric cements of the present invention having pendent vinylgroups from IEM grafted and polymerized via photo-initiation, usingdifferent vinyl-containing monomers as a comonomer including aminoacids, acrylic acid, and HEMA, wherein HEMA=2-hydroxyethyl methacrylate;MASPA=methacryloyl aspartic acid; AGA=acryloyl glutamic acid;ABA=acryloyl beta-alanine; MGA=methacryloyl glutamic acid;MBA=methacryloyl beta-alanine; AASPA=acryloyl aspartic acid; andAA=acrylic acid.

FIG. 7 is a graph illustrating compressive strengths and viscosities ofionomeric cements of the present invention having pendent vinyl groupsfrom IEM grafted and polymerized via photo-initiation, with differentformulations of IEM grafted terpolymer/methacryloyl beta-alanine/water.

FIG. 8 is a bar graph illustrating compressive strengths of ionomericcements of the present invention having pendent vinyl groups from IEMgrafted and polymerized via photo-initiation, at different powder/liquidratios, using methacryloyl beta-alanine as a comonomer.

FIG. 9 is a bar graph illustrating compressive, diametral tensile andflexural strengths of ionomeric cements of the present invention havingpendent vinyl groups from IEM grafted and polymerized viaphoto-initiation, as compared to a commercial GC Fuji II LCglass-ionomer cement.

DETAILED DESCRIPTION

The term “ionomer” refers to a polymer or copolymer having sufficientpendent ionic groups to undergo a setting reaction or curing reaction inthe presence of a reactive filler material and water. Water serves as areaction medium facilitating the transport of ions between the ionomerand the filler, thereby allowing the acid-base chemical cure settingreaction to occur.

By the term “reactive filler”, it is meant a powdered or otherwisesurface-active metal oxide or hydroxide, mineral silicate, or ionleachable glass or ceramic, that is capable of reacting with the ionomerin the presence of water to form a hydrogel. Representative examples ofreactive filler materials include calcium-containing andaluminum-containing materials such as calcium alumino silicate glass,calcium alumino fluorosilicate glass, calcium aluminumfluoroborosilicate glass, and like materials known in the art ofglass-ionomer cements. In embodiments wherein the cement is used fordental purposes, reactive powders that contain leachable fluorides maybe beneficial from the standpoint of cariostatic prevention. Examples ofsuch powders are fluoroaluminosilicate and fluoroaluminoborateion-leachable glasses.

Polymerizable acids used for preparing ionomers useful for glass-ionomercement systems include alkenoic acids and unsaturated mono-, di- andtricarboxylic acids. Representative alkenoic acids are described, forexample, in U.S. Pat. Nos. 3,655,605; 4,016,124; 4,089,830; 4,143,018;4,342,677; 4,360,605; 4,376,835 and 5,130,347. Specific examples areacrylic acid, maleic acid, fumaric acid, itaconic acid, crotonic acid,methacrylic acid, the acid chlorides thereof and the acid anhydridesthereof and chloro or bromo derivatives thereof. Particularly preferredmonomers are acrylic acid (AA), itaconic acid (IA) and maleic acid (MA),and the chlorides or anhydrides thereof.

The incorporation of naturally occurring amino acids to glass-ionomerbone cements of the present invention promotes biocompatability andenhances mechanical properties. In addition, their incorporation leadsto better handling characteristics at higher molecular weight comparedto poly (acrylic) acid homopolymers or acrylic acid/itaconic acidcopolymers. The amino acid-containing monomer that is used in thepresent invention may be naturally occurring or synthetic in nature.Examples are glycine, glycylglycine, alanine, valine, leucine,isoleucine, phenylalanine, tyrosine, proline, hydroxyproline, serine,threonine, 3-amino-3-methylbutanoic acid, 6-aminocaproic acid,aminobenzoic acid (meta and para), 4-aminosalicylic acid, iminodiaceticacid, lanthionine, methionine, aspartic acid, glutamic acid, lysine,delta-aminolevulinic acid, beta-alanine, alpha-aminobutyric acid,gamma-aminobutyric acid, gamma, epsilon-diaminopimelic acid, gamma,alpha-diaminobutyric acid, ornithine, omega-aminododecanoic acid,beta-cyanoalanine, epsilon-methylhistidine, canavanine, djenkoic acid,1-azaserine, gamma-methylene glutamic acid, N-methyl tyrosine, arginine,tryptophan, norvaline, cystine, cysteine, and hydroxylysine.

Preferred amino acids contain acryloyl or methacryoyl groups. Specificexamples include acryloyl beta-alanine (ABA), acryloyl glycine (AG),acryloyl aspartic acid (AASPA), acryloyl glutamic acid (AGA), acryloyl6-aminocaproic acid (AbACA, methacryloyl beta-alanine (MBA),methacryloyl glycine (MG), methacryloyl aspartic acid (MASPA),methacryloyl glutamic acid (MGA) and methacryloyl 6-aminocaproic acid(M6ACA) and methacryloyl methionine (MMET). The many other polypeptidefragments known to those skilled in the art may also be treatedaccording to the present invention with acryloyl or methacryloyl acidchloride or anhydride to produce new monomers suitable for the polymersin the cements of the present invention. For example, the dimer ofglutamic acid, glycine-glutamic acid peptide unit, etc., reaction withacryloyl chloride would produce a monomer having high acid and amidegroup content and thereby be useful herein. The acryloyl or methacryloylderivatives of amino acids are prepared by known synthetic techniques.See, for example, U.S. Pat. No. 5,369,142 to Culbertson, and Kao et al.,Dent. Mater 12: 44-51 (1996).

Preferred copolymers of the present invention are terpolymers having thefollowing formula: Poly(AA-IA-AGA); Poly(AA-IA-MGA); Poly(AA-IA-AG);Poly(AA-IA-MG); Poly(AA-IA-ABA); Poly(AA-IA-MBA); Poly(AA-IA-A6ACA); andPoly(AA-IA-M6ACA). In some embodiments of the present invention, thecement composition contains two or more such copolymers. Preferredcombinations include blends of Poly (AA-IA-MGA)/Poly(IA-IA-M6ACA),Poly(AA-IA-MGA)/Poly(AA-IA-MG) and Poly(AA-IA-AASPA)/Poly(AA-IA-MG). Therelative amounts of copolymers range from about 10% to about 90% bytotal weight of copolymers. In preferred embodiments, the copolymers arepresent in roughly equal amounts, e.g., each about 50% by weight. Inother embodiments, the cement contains at least one additional polymeror copolymer known in the art e.g., poly AA, poly IA, copolymers of AAand IA, etc. The addition of these elements may improve toughness anddecrease brittleness of the ultimate cement composition.

The pendent carboxylic acid groups on the copolymer must be sufficientin number or percent by weight to bring about the setting or curingreaction in the presence of the reactive powder. To create a source ofadditional covalent cross-linking, which imparts additional strength tothe ultimate ionomeric cement composition, a portion of the carboxylicacid groups is reacted with a bi-functional monomer. Suitablebi-functional monomers are water soluble and undergo a reaction with acarboxylic acid group to form a covalent bond, while maintaining apolymerizable functional group capable of addition polymerization. Thus,one functionality of this monomer facilitates grafting on to thecopolymer backbone via the carboxylic acid groups. In preferredembodiments, such functionalities contain nucleophilic groups such ashydroxyl, amine, isocyanato and epoxy. The other functionality is apolymerizable functional group capable of addition polymerization.Preferred polymerizable functional groups include ethylenicallyunsaturated groups such as vinyl groups, and epoxy groups. In otherpreferred embodiments, the bi-functional monomer further contains atleast one carboxyl or hydroxyl group to enhance water solubility of thecopolymer. Examples of suitable bi-functional monomers include acryloylchloride, methacryloyl chloride, vinyl azalactone, allyl isocyanate,2-hydroxyethylmethacrylate (HEMA), 2-aminoethylmethacrylate,2-isocyanatoethyl methacrylate (IEM), acrylic acid, methacrylic acid andN-vinylpyrrolidone. Other examples of suitable bi-functional monomersare described in U.S. Pat. No. 4,035,321 and on columns 5-7 of U.S. Pat.No. 5,130,347 to Mitra. Preferred bi-functional monomers are the aminoacid-containing monomers described herein, GM, IEM and HEMA. In general,the bi-functional monomer is present in an amount of from about 5 toabout 50%, and preferably from about 10 to about 25%, based upon themole fractions of the copolymer and the bi-functional monomer.

To effect the additional cross-linking of the cement, one or morecomonomers are included in the cement composition. The comonomercontains at least one polymerizable functional group reactive with thepolymerizable functional groups on the copolymer backbone (provided bythe bifunctional monomer). Suitable polymerizable functional groups inthe comonomers include but are not limited to ethylenically unsaturatedgroups (e.g., alkenyl groups and preferably vinyl groups) and epoxygroups. Ethylenically unsaturated groups, especially those that can bepolymerized by means of a free radical mechanism e.g., substituted andunsubstituted acrylates, methacrylates, alkenes and acrylamides, arepreferred. In aqueous systems, polymerizable groups that are polymerizedby a cationic mechanism e.g., polymerizable ethylenically unsaturatedgroups such as vinyl ether groups and polymerizable epoxy groups, areless preferred since a free radical mechanism is typically easier toemploy in such systems than a cationic mechanism. Preferred comonomersinclude the amino acid-containing monomers described herein. Morepreferred comonomers are acryloyl beta-alanine, methacryloylbeta-alanine, acryloyl glutamic acid and methacryloyl glutamic acid. Ingeneral, the comonomer is present in the ultimate cement composition inan amount of from about 10% to about 60%, preferably from about 15 toabout 50%, and more preferably from about 20 to about 35%, based uponthe total weight of the total copolymer/comonomer/water mixture.

Methods for preparing the ionomeric copolymers e.g., via free-radicalpolymerization, are well known. (See, Crisp et al., “Glass ionomercement formulations. II. The synthesis of novel polycarboxylic acids,”in J. Dent. Res. 59 (6): 1055-1063 (1980)). In preferred embodiments,the ionomeric copolymer is prepared first and then the polymerizablefunctional groups are added (e.g., grafted thereon). This sequencesubstantially eliminates integration of the functional groups into thecopolymer backbone. General procedures of grafting pendent polymerizablegroups onto the ionomeric copolymers are known in the art e.g., U.S.Pat. No. 5,130,347.

The relative proportions of monomers and comonomer vary depending uponthe desired properties of the cement e.g., orthopaedic or dental. Inembodiments wherein the amino acid containing monomer is part of thecopolymer backbone, the molar ratio of the total amount of othermonomer(s) to the amino acid ranges from about 7:1 to about 11:1. Inpreferred embodiments of the present invention wherein the copolymercontains acrylic acid, itaconic acid and an amino acid, preferably anacryloyl- or methacryloyl amino acid, molar ratios of acrylic acid toitaconic acid to amino acid range from about 10:1:1 to about 5:2:1, andmore preferably about 8:2:1 respectively. Likewise, the number averagemolecular weight (Mn) generally varies from about 3,500 to about 110,000daltons, and preferably from about 5,500 to about 80,000 daltons.

To prepare the ionomeric cement, the copolymer is mixed with thereactive powder and the comonomer in the presence of water. Thecomponents of the ionomeric cement system can be combined (such as bymixing or blending) in a variety of manners and amounts in order to formthe ionomeric cements of this invention. Suitable combining techniquesinclude those commonly employed to mix ionomer cement systems. In onetechnique, a concentrated aqueous solution of the copolymer andcomonomer (i.e., ionomer) is mixed with reactive powder at the time ofuse. The resultant combination of ionomer, reactive powder and waterallows the setting reaction to begin. In another technique, the ionomerand powder are provided as a freeze-dried or lyophilized powdered blendunder substantially anhydrous conditions i.e., conditions in which thereis not sufficient water to allow the setting reaction to proceed. Suchsystems can then be combined with water at the time of use in order tobegin the setting reaction. Once the setting reaction has begun, theresultant mixture may be formed into its desired shape, followed bycuring and allowing the mixture to fully harden.

In general, the weight-to-weight ratio of the copolymer(s) to water isfrom about 1:9 to about 9:1. In general, the concentration of copolymerin water ranges from about 30 to about 70% by weight, and preferablyfrom about 40 to about 65 percent. The resultant aqueous solution has aratio of polymer to liquid generally ranging from about 1.5 to about 8.

In addition to the particular polymerization initiation system, thereaction mixture may also include a modifying agent such as tartaricacid, thereby providing the ability to achieve a longer working time anda shorter setting time, respectively, when preparing the cement. Theterm “working time” is generally regarded as referring to the timebetween the beginning of the setting reaction when the ionomer andreactive powder are combined in the presence of water, and the time thesetting reaction proceeds to the point when it is no longer practical toperform further physical work upon the system, e.g. spatulate it orreshape it, for its intended dental or medical application. The term“setting time” refers to the time measured from the beginning of thesetting reaction in a restoration to the time sufficient hardening hasoccurred to allow subsequent clinical or surgical procedures to beperformed on the surface of the restoration. In the setting reaction,the reactive filler behaves like a base and reacts with the acidicionomer to form a metal polysalt which acts as the binding matrix. Thesetting reaction is therefore characterized as a chemical cure systemthat proceeds automatically upon mixing the ionomer and reactive fillermaterial in the presence of water. The cement sets to a gel-like statewithin a few minutes and rapidly hardens to develop strength. See e.g.,Prosser et al., J. Chem. Tech. Biotechnol. 29: 69-87 (1979). Tartaricacid and other chelating agents have proven useful in modifying thesetting rate such as to provide longer working times for the cements.See e.g., U.S. Pat. Nos. 4,089,830, 4,209,434, 4,317,681 and 4,374,936.In general, an increase in working time results in an increase insetting time as well.

The ratio of powder (i.e., reactive powder or powdered blend of ionomerand reactive powder) to liquid affects the workability of the mixedionomer cement systems. Ratios higher than about twenty to one (powderto liquid, by weight) tend to exhibit poor workability, while ratiosbelow about one to one tend to exhibit poor mechanical properties, e.g.,strength, and hence are not preferred. Preferred ratios are on the orderof about 1:3 to about 6:1 and preferably about 1:1 to 4:1 for thereactive powder (i.e., glass plus reducing agent) to liquid system,(copolymer, comonomer and water) and about 1:1 to 16:1 and preferablyabout 4:1 to 14:1 for the powdered blend system (i.e., glass, reducingagent, copolymer and comonomer). Higher glass (i.e., powder) contentslead to materials with higher compressive strengths, while lower glasscontents lead to materials with high flexural strengths and toughness.

Other ingredients, such as polymerization initiators, modifying agentsand co-solvents can be added at any time and in any manner that does notprematurely begin the setting reaction or the photo-curing reaction.Modifying agents can be used in the ionomer cement systems of thepresent invention in order to provide prolonged working times.

The cements are polymerized in accordance with known techniques. Atleast one initiator is required for most polymerization methods such asthose based on oxidation/reduction reactions and ultraviolet and visiblelight. Photo-initiators promote free radical cross-linking of theethylenically unsaturated component on exposure to light of a suitablewavelength and intensity. It should also be sufficiently shelf-stableand free of undesirable coloration to permit storage and use undertypical medical or dental conditions. The photo-initiator preferably iswater-soluble or water-miscible. Photo-initiators bearing polar groupsusually possess a sufficient degree of water-solubility orwater-miscibility to qualify for this use. The photo-initiator can beused alone but it may be used in combination with a suitable donorcompound or accelerator (e.g., amines, peroxides, phosphorus compounds,ketones and alpha-diketone compounds). Preferred visible light-inducedinitiators include camphoroquinone (which typically is combined with asuitable hydrogen donor such as an amine), diaryliodonium simple ormetal complex salts, chromophore-substituted halomethyl-s-triazines andhalomethyl oxadiazoles. Particularly preferred visible light-inducedphoto-initiators include combinations of an alpha-diketone e.g.,camphoroquinone, and a diaryliodonium salt, e.g., diphenyliodoniumchloride, bromide, iodide or hexafluorophosphate, with or withoutadditional hydrogen donors (such as sodium benzene sulfinate, amines andamine alcohols). Preferred ultraviolet light-induced polymerizationinitiators include ketones such as benzyl and benzoin, and acyloins andacyloin ethers.

The photo-initiator should be present in an amount sufficient to providethe desired rate of photo-polymerization. The amount depends on factorsincluding the light source, the thickness of the cement layer to beexposed to radiant energy and the extinction coefficient of thephoto-initiator. In general, the photo-initiator components are presentat a total weight of about 0.01 to about 5%, preferably from about 0.1to about 5%, based on the total weight (including water) of the unsetcement components.

Initiation of polymerization based on oxidation/reduction (“redox”)reactions entails the reaction or cooperation between a reducing agentand an oxidizing agent to produce free radicals that in turn initiatepolymerization of the pendant functional groups on the ionomericcopolymer. Like photo-initiators, redox reagents exhibit adequatestorage stability and lack of colorization under typical conditions ofuse. In addition, they should be sufficiently water-soluble to permitready dissolution in (and discourage separation from) the othercomponents of the cement. They are present in an amount sufficient topermit an adequate free-radical reaction rate. In general, these amountsrange from about 0.01 to about 10%, and preferably from about 0.02 toabout 5%, based on the total weight (including water) of the unsetcement components.

Reducing agents (also termed “activators”) include ascorbic acid, cobalt(II) chloride, ferrous chloride, ferrous sulfate, hydrazine,hydroxylamine (depending upon the choice of oxidizing agent) oxalicacid, thiourea, and salts of a dithionite or sulfite anion. Preferredreducing agents include ascorbic acid and ferrous sulfate. Oxidizingagents (also termed “initiators”) include cobalt (III) chloride,tert-butyl hydroperoxide, ferric chloride, hydroxylamine (depending uponthe choice of reducing agent), perboric acid and its salts, and salts ofa permanganate or persulfate anion. Preferred oxidizing agents arepotassium persulfate, ammonium persulfate and hydrogen peroxide.

Microencapsulation of the reducing agent enhances storage stability andallows the reducing agent and oxidizing agent to be packaged together.Water-soluble and water-insoluble encapsulants can be employed;water-insoluble encapsulants are preferred because they generallyprovide better long-term storage stability under moist or humidconditions. Suitable encapsulating materials include cellulosicmaterials as cellulose acetate, cellulose acetate butyrate, ethylcellulose, hydroxymethyl cellulose and hydroxyethyl cellulose beingpreferred. Other encapsulants include polystyrene, copolymers ofpolystyrene with other vinylic monomers and polymethylmethacrylate,copolymers of methylmethacrylate with other ethylenically-unsaturatedmonomers. Preferred encapsulants are ethylcellulose (EC) and celluloseacetate butyrate (CAB). By varying the choice of encapsulant and theencapsulation conditions, the onset of curing can be tailored to startat times ranging from seconds to minutes. Additional optimization of theencapsulation process allows the mixing and setting times to becustomized to a delivery system or to the needs of a specific clinicalprocedure. The ratio of amount of encapsulant to activator generallyranges from 0.5 to about 10 and preferably from about 2 to about 6.

Typically, the copolymer(s) and comonomer are packaged together.Depending upon the application of the cement and the manner in whichpolymerization is achieved, various components of the cementcompositions may be packaged differently. For example, in the case of aredox-based system, ingredients of the cement composition are dividedinto two separate packages—the first package containing the copolymer,comonomer, the initiator (i.e., oxidizing agent) and water, and thesecond package containing the reactive filler and the activator (i.e.,the reducing agent). In another embodiment, the first package containsall solid materials (e.g., copolymer, comonomer, reactive filler and ifdesired, the reducing agent, and the second package contains water andif desired, the initiator. In the case of photo-initiation, thephoto-initiator can be included in either the solid (e.g. paste) orliquid parts of the cement.

The cements of the present invention may further contain pigments,nonvitreous fillers, polymerization inhibitors e.g., hydroxytoluene,free radical scavengers e.g., 4-methoxyphenol, butylated hydroxytoluene(BHT), reactive and nonreactive diluents e.g., 2-hydroxyethylmethacrylate, hydroxypropyl methacrylate, surfactants (such as toenhance solubility of an inhibitor e.g., polyoxyethylene) and couplingagents to enhance reactivity of fillers e.g., 3-(trimethoxysilyl)propylmethacrylate. The amount of inhibitor added ranges from about 0.001 toabout 2% and preferably from about 0.02 to about 0.5% based on the totalweight of the copolymer/comonomer/water mixture. BHT is a preferredinhibitor. It is employed in conjunction with a surfactant (in an amountof about 1%) to enhance solubility.

The cements of the present invention can be used in a variety ofapplications in the dental and medical fields. Dental applicationsinclude restoratives for lining or basing, cementation, sealants and asadhesives and bulk filling. Orthopaedic applications include cements forprosthetic joint (e.g., knee and hip) replacement, bone grafts, andrepair of bony defects from disease or trauma.

The invention will now be illustrated by way of the following examples.They are not intended to limit the scope of the presently disclosedinvention in any way. Unless indicated otherwise, all parts are byweight.

EXAMPLE 1 Synthesis of Methacryloyl L-glutamic Acid (MGA)

NaOH (60 g, 1.5 mol) was dissolved in 250 ml of water and cooled down toaround 15° C. L-Glutamic acid (73.6 g, 0.5 mol) was then dissolved inthe NaOH aqueous solution. To a three-neck flask, equipped with athermometer and a mechanical stirrer, containing L-glutamic acid andNaOH aqueous solution, and cooled down to 0 to 5° C., methacryloylchloride (48.9 ml, 0.5 mol) was added dropwise with vigorous stirringwithin about one hour while keeping the temperature below 5° C. Anadditional hour was allowed to complete the reaction after the additionwas completed. The solution was acidified to pH=2 with a solution ofconcentrated HCl (37%) and distilled water (1:1, v/v), oversaturatedwith NaCl at room temperature, and extracted three to four times withwarm ethyl acetate (50-60° C.). The extracted solution was separatedusing a separation funnel, dried with anhydrous MgSO₄, filtered with aBuchner funnel, and concentrated using a rotary vacuum evaporator toobtain white crystals. The rectangular and transparent crystals wereobtained by recrystallization from ethyl acetate.

EXAMPLE 2 Synthesis of Methacryloyl Glycine (MG)

The same procedure, as described in synthesis of methacryloyl L-glutamicacid, was utilized with glycine (37.5 g, 0.5 mol), NaOH (40 g, 1.0 mol),water (250 ml), and methacryloyl chloride (48.9 ml, 0.5 mol) to yield awhite crystalline material. Needle-like and transparent crystals wereobtained after recrystallization from warm ethyl acetate (50-60° C.).

EXAMPLE 3 Synthesis of Methacryloyl L-aspartic Acid (MASPA)

A similar procedure, as described in synthesis of methacryloylL-glutamic acid, was utilized with L-aspartic acid (66.6 g, 0.5 mol),NaOH (60 g, 1.5 mol), water (250 ml), and methacryloyl chloride (48.9ml, 0.5 mol) to yield a white slurry and viscous material. After beingrefrigerated overnight, white crystals precipitated out of the slurrymaterial. The white crystals were dried under vacuum at 25° C. afterwashed using hexane.

EXAMPLE 4 Synthesis of Methacryloyl Beta-Alanine (MBA)

A similar procedure, as described in synthesis of methacryloylL-glutamic acid, was utilized with beta-alanine (44.5 g, 0.5 mol), NaOH(40 g, 1.0 mol), water (250 ml), and methacryloyl chloride (48.9 ml, 0.5mol) to yield a white crystalline material, which was dried under vacuumat 25° C. after being washed with hexane.

EXAMPLE 5 Synthesis of Methacryloyl 6-aminocaproic Acid (M6ACA)

A similar procedure, as described in synthesis of methacryloylL-glutamic acid, was utilized with 6-aminocaproic acid (65.6 g, 0.5mol), NaOH (40 g, 1.0 mol), water (250 ml), and methacryloyl chloride(48.9 ml, 0.5 mol) to yield a light yellow oily organic material. Afterbeing refrigerated overnight, light yellow crystals precipitated out ofthe oily material. The yellowish crystals were dried under vacuum at 25°C.

EXAMPLE 6 Synthesis of Methacryloyl D,L-methionine (MMET)

A similar procedure, as described in synthesis of methacryloylL-glutamic acid, was utilized with D,L-methionine (74.6 g, 0.5 mol),NaOH (40 g, 1.0 mol), water (250 ml), and methacryloyl chloride (48.9ml, 0.5 mol) to yield a light yellow, slightly odiferous crystallinematerial which was dried under vacuum at 25° C.

EXAMPLE 7 Synthesis of Acryloyl L-Glutamic Acid (AGA)

The same procedure, as described in synthesis of methacryloyl L-glutamicacid, was utilized with L-glutamic acid (147.1 g, 1.0 mol), NaOH (120 g,3.0 mol), water (350 ml), and acryloyl chloride (81.3 ml, 1.0 mol) toyield a white crystalline material. Cubic and transparent crystals wereobtained after recrystallization from warm ethyl acetate (50-60° C.) anddrying under vacuum at 25° C.

EXAMPLE 8 Synthesis of Acryloyl Glycine (AG)

The same procedure, as described in synthesis of methacryloyl L-glutamicacid, was utilized with glycine (75.1 g, 1.0 mol), NaOH (80 g, 2.0 mol),water (350 ml), and acryloyl chloride (81.3 ml, 1.0 mol) to yield awhite crystalline material. Cubic and transparent crystals were obtainedafter recrystallization from warm ethyl acetate (50-60° C.) and dryingunder vacuum at 25° C.

EXAMPLE 9 Synthesis of Acryloyl L-Aspartic Acid (AASPA)

The similar procedure, as described in synthesis of methacryloylL-glutamic acid, was utilized with L-aspartic acid (133.1 g, 1.0 mol),NaOH (120 g, 3.0 mol), water (350 ml), and acryloyl chloride (81.3 ml,1.0 mol) to yield a white slurry and viscous material. After beingrefrigerated overnight, white crystals precipitated out of the slurrymaterial. The white crystals were dried under vacuum at 25° C. afterbeing washed with hexane.

EXAMPLE 10 Synthesis of Acryloyl Beta-Alanine (ABA)

The same procedure, as described in synthesis of methacryloyl L-glutamicacid, was utilized with beta-alanine (89.1 g, 1.0 mol), NaOH (80 g, 2.0mol), water (350 ml), and acryloyl chloride (81.3 ml, 1.0 mol) to yielda white crystalline material, which was dried under vacuum at 25° C.after washing with hexane.

EXAMPLE 11 Synthesis of Acryloyl 6-aminocaproic Acid (A6ACA)

The general procedure was similar to that described in synthesis ofmethacryloyl L-glutamic acid. To an aqueous solution of 6-aminocaproicacid (131.2 g, 1.0 mol), NaOH (80 g, 2.0 mol), and water (350 ml),acryloyl chloride (81.3 ml, 1.0 mol) was added dropwise for about oneand one half hours. After reaction was complete, the solution wasacidified to pH=2 with a solution of concentrated HCl (37%) anddistilled water (1:1, v/v), and oversaturated with NaCl at roomtemperature. The white slurry and crystalline materials were extractedthree to four times with warm ethyl acetate (50-60° C.). The extractedsolution was separated using a separation funnel, dried with anhydrousMgSO₄, filtered with a Buchner funnel, and concentrated using a rotaryvacuum evaporator to obtain white fine crystals. These fine crystalswere dried under vacuum at 25° C.

Yield and melting point of the synthesized monomers in Examples 1-11 areshown in Table 1. TABLE 1 Yield and Melting Point of the Monomers CodeYield (%) Melting Point (° C.) AGA 34-38 116-118 MGA 48-55 128-130 AG33-35 128-130 MG 55-68 104-105 ABA 46 84-86 MBA 62 66-69 A6ACA 92 72-76M6ACA 76 87-90 AASPA 25 135-138 MASPA 56 93-96 MMET 44 71-72

EXAMPLE 12 One-Pot Synthesis of Poly(Acrylic Acid-co-ItaconicAcid-co-Methacryloyl Glutamic Acid) with Pendent 2-IsocyanatoethylMethacrylate (IEM)

The general reaction scheme is illustrated in FIG. 1. To a three-neckflask, equipped with a thermometer, a nitrogen inlet, a condenser, adrop funnel and a mechanical stirrer, containing2,2′-azobisisobutyronitrile (AIBN) (0.2645 g) and 125 ml oftetrahydrofuran (THF), a liquid mixture of AIBN (0.2625 g), acrylic acid(AA), (27.38 ml), itaconic acid (IA) (12.99 g) and methacryloyl glutamicacid MGA (10.74 g) and 150 ml of THF were added in about one hour.Before the reaction was initiated, the system was purged with N₂ for 30min. to displace the dissolved oxygen and then the temperature wasraised to around 62-64° C. Nitrogen purging was continued until thereaction was completed. After completion of the additions, thepolymerization was run for an additional 10-12 hours at the sametemperature. The molar feed ratio for the terpolymer was 8:2:1(AA:IA:MGA).

The above solution was then cooled down to 35-40° C. and kept at thistemperature until the reaction was completed. To the solution, 0.09 g ofbutylated hydroxy-toluene (BHT), 0.09 g of triphenylstibine (TPS) and0.6 g of dibutyltin dilaurate (DBTL) were added. After the solutionbecame clear, a mixture of 27.07 g of IEM and 27 ml of THF were addeddropwise within 1.5 hours. Another two-hour period was used to completethe reaction. Both FTIR (Fourier transform-infrared spectroscopy) and¹H-NMR (proton nuclear magnetic resonance spectroscopy) were used tomonitor the reaction.

The terpolymer grafted with IEM was recovered by precipitation fromdiethyl ether, followed by drying in a vacuum oven at room temperature.

The grafted terpolymer was characterized by FT-IR (NMR). The FT-IRspectra were obtained with a FT-IR Spectrometer (Model 1600 FTIR, ThePerkin Elmer Co., Norwalk, Conn.), where the sample film was cast on theNaCl crystal. ¹H NMR spectra were obtained on a Bruker AM 400 MHz NMRspectrometer using deuterated dimethylsulfoxide as solvent.

EXAMPLE 13 One-Pot Synthesis of Poly(Acrylic Acid-co-Itaconic Acid) withPendent Glycidyl Methacrylate (GM)

The same procedure, as described in the synthesis of poly(acrylicacid-co-itaconic acid-co-methacryloyl glutamic acid), was used toproduce the poly(acrylic acid-co-itaconic acid) copolymer with the molarfeed ratio of 7:3.

The formed solution was then cooled down to around 62° C. and kept untilreaction was completed. To the solution, 1.05 g of BHT and 3.15 g ofN,N-dimethylaniline (DMA) were added. After the solution became clear, amixture of 30.0 g of GM and 30 ml of THF were added dropwise withinabout 1.5 hours. Another 30-hour period was used to complete thereaction. Both FTIR and ¹NMR were used to trace the reaction.

The copolymer grafted with GM was recovered by precipitation fromdiethyl ether, followed by drying in a vacuum oven at room temperature.

The grafted terpolymer was identified by FT-IR and nuclear magneticresonance (NMR). The FT-IR spectra were obtained with a FT-IRSpectrometer, where the sample film was cast on the NaCl crystal. ¹H NMRspectra were obtained on a Bruker AM 400 MHz NMR spectrometer usingdeuterated dimethyl-sulfoxide as a solvent.

EXAMPLE 14 One-Pot Synthesis of Poly(Acrylic Acid-co-ItaconicAcid-co-Methacryloyl Glutamic Acid) with Pendent Glycidyl Methacrylate(GM)

A similar procedure, as described in Example 12 for synthesis ofpoly(acrylic acid-co-itaconic acid-co-methacryloyl glutamic acid) withthe molar feed ratio of 8:2:1 and in Example 13 for GM grafting, wasused to produce the desired terpolymer with pendent vinyl functionality.

EXAMPLE 15 Microencapsulation of Ascorbic Acid in Cellulose AcetateButyrate (CAB)

Into a round bottom flask containing 150 ml of ethyl acetate, 2.0 g ofcellulose acetate butyrate (CAB, MW=200,000, butyrate content=17%) wasadded and dissolved for about 2-3 hours to form a homogenous solution. Awater bath was placed under the flask for cooling later. Then 1.0 g ofascorbic acid was added and suspended in the solution for about 15 to 30minutes, with stirring. 150-200 ml of n-hexane was added dropwise at therate of 80-100 drops per min. After completion of addition of n-hexane,ice water was added into the bath to harden the formed microcapsules.After 5-10 minutes, cold n-hexane was added to wash the microcapsules.

The microcapsules were recovered by decantation, washed with coldn-hexane, and air-dried or vacuum-dried.

EXAMPLE 16 Formulation and Preparation of Vinyl-Containing HybridGlass-Ionomer Bone Cements Using Redox Initiators

A two-component system (liquid and solid) was used for formulating redoxinitiator containing hybrid glass-ionomer cements. The liquid componentcontaining an oxidizer was made by mixing vinyl containing terpolymer(40-60% of total liquid, wt %) with K₂S₂O₆ (0.1-0.5%), butylatedhydroxytoluene (BHT, 0.2-0.8%), polyoxyethylene nonylphenol (PEONP,0.6%), vinyl-containing amino acid (20-30%) and distilled water(15-30%). The solid component containing a reducing agent was preparedby mixing GC Fuji II LC™ glass powder (GC American Dental Co.) withascorbic acid containing microcapsules (0.2-0.6% of glass powder, wt %),using a vortex with a maximal speed. A powder/liquid ratio (P/L) of1.0-2.5/1 was used in the formulation. A typical formulation is shown inTable 2. TABLE 2 Two-Component Redox Glass-Ionomer Bone Cement PowderLiquid Composition Commercial Fuji II LC 50 (wt %) Poly(acrylic glass(GC America) acid-co-itaconic acid-co- *ascorbic acid, glutamic acid)grafted encapsulated with with 15% 2- cellulose acetate isocyanatoethylbutyrate, 0.4% of methacrylate (mol % of glass (wt %). polyacid). *Ratioof ascorbic 18 (wt %) Acryloyl beta- acid/cellulose acetate alanine(comonomer) butyrate = 1/3 (wt/wt). 32 (wt %) Distilled water 0.1 (wt %)K₂S₂O₈ 0.2 (wt %) Butylated hydroxytoluene (inhibitor) 0.6 (wt %)Polyoxyethylene nonylphenol P/L ratio 2-2.5 1 (wt/wt)

EXAMPLE 17 Estimates of Curing Time of the Redox System

A metal rod was used to evaluate the working time. The rod was insertedinto the center of a mixture of the cement, which was mixed and packedinto a small vial with a hole at the bottom. Working time was recordedonce the mixing process was initiated. The moment at which the metal rodcould not be manually moved in the cement measured from the time ofmixing, is defined as the working time. The working times estimated areshown in Table 3. TABLE 3 Working Time of Self-Cured Hybrid GI BoneCement* Ratio acid encapsulant, (ascorbic Working Time Code Encapsulantwt/wt) vs. (min, observed) XMG1 ethyl cellulose 1:1 1 XMG2 ethylcellulose 1:2 2 XMG3 ethyl cellulose 1:3   2-3.5 XMG4 cellulose acetate1:2 4-5 butyrate XMG5 cellulose acetate 1:3 5-6 butyrate*Fuji II LC glass was used to make formulations. The polymer liquid wasmade in formulation of 50/20/30 (grafted terpolymer/ABA/water).

EXAMPLE 18a Specimen Preparation Using Redox Initiators

Polymer solutions were made as described in example 15. GC Fuji II LC™glass powder was supplied by GC American Dental Co. and used inaccordance with manufacturer's instructions. The glass powder versuspolymer liquid (P/L) ratio was in the range of 1.5 to 2.5.

Specimens were mixed and fabricated at room temperature, according tomanufacturer's instructions. The cylindrical specimens were prepared inmolds made of glass tubing, with dimensions of 4 mm diameter by 8 mmlength and 4 mm diameter by 2 mm length for compressive (CS) anddiametral tensile strength (DTS) tests, respectively. The specimens forthe flexural strength (FS) test were prepared using a rectangular Teflonmold with dimensions of 3 mm width by 3 mm depth by 25 mm length. Thespecimens were removed from molds after 15-20 minutes, and conditionedin distilled water at 37±2° C. for 1 day or 1 week, prior to testing.

EXAMPLE 18b Specimen Preparation Using Visible Light Initiators

The formulations for light-curable materials were made by mixing thevinyl containing terpolymers with 0.5% (wt/wt) of d,l-camphoroquinone(CQ), 1% (wt/wt) of diphenyliodonium chloride (DC), 2-hydroxyethylmethacrylate (HEMA) or vinyl-containing amino acid (i.e., AGA or ABA)and distilled water. Glass powder used in this study was the powder usedin the Vitremer tri-cure glass-ionomer system (3M Dental Products), witha powder/liquid ratio (P/L) of 2.5/1 as recommended by 3M DentalProducts. Four to five specimens for each formulation were prepared forflexural strength (FS) tests. Specimens were fabricated similar to theprocedures as described in Example 17, except that the curing processwas completed by using an EXAKT 520 Blue Light Polymerization Unit(9W/71, GmbH, Germany) and a split Teflon mold with a glass window forlight exposure was used. The specimens were removed from molds after15-20 minutes, and conditioned in distilled water at 37±2° C. for 1 dayor 1 week, prior to testing.

EXAMPLE 18c Strength Measurements

Testing of specimens was performed on a screw-driven mechanical testingmachine (Model Sintech/2G, MTS Systems Corp., Eden Prairie, Minn., USA),with a crosshead speed of 1 mm/min for both diametral tensile strength(DTS) and flexure strength (FS) measurements. The FS test was performedin three-point bending, with a span of 20 mm between supports. Thesample sizes were n=5 to 9 for all three tests.

The diametral tensile strength was determined from the relationshipDTS=2P/πdt, where P=the load at fracture, d=the diameter of the cylinderand t=the thickness of the cylinder. The flexure strength in three-pointbending was obtained using the expression FS=3Pl/2 bd², where P=the loadat fracture, l=the distance between the two supports, b=the breadth ofthe specimen, and d=the depth of the specimen.

To establish controls, the Fuji II glass ionomer (GC America), Vitremerlight-cured glass-ionomer (3M Dental product), and Fuji II light-curedcontrol (GC America) (commercially available) were prepared permanufacturing directions for comparison and model systems. Theirmechanical strengths are shown in all the related tables and figures.

EXAMPLE 18d Bond Strength Measurement

Freshly extracted human molars were embedded in acrylic resin with thebuccal surface facing up. The specimens were ground using a series SiCpapers (240, 400, and 600 grit) to expose a superficial dentin surface.A Teflon mold having a cylindrical hole 2 mm in diameter and 5 mm indepth was secured over the dentin surface to establish a bonding area.Two groups of bonded specimens were prepared for each formulation. Inthe first group, the 600 grit surface was bonded directly. In the secondgroup, the dentin surface was treated with 37% phosphoric acid gel for15 seconds and then washed and dried of excess water using an airsyringe. All surfaces were kept moist until bonded. A thin layer ofadhesive liquid with no glass was placed on the dentin surface and curedfor 10 seconds. The cement mix was then placed in the cavity to achievea thickness of 2 mm and photocured for 40 seconds using a Demetron(Demetron Corp.) light-curing unit. The mold was removed and the sampleswere stored 24 hours at 37° C. before shear testing.

The shear test was conducted by securing the samples in a SynTechtensile tester (MTS Systems, Minneapolis, Minn.) with the bondedspecimen perpendicular to the crosshead containing a knife-edge shearingblade. The surface of the tooth was brought flush to the shear blade andsecured so that the blade hit at the junction of the bonded specimen andthe tooth substrate. The test was run at 0.5 mm/minute. The shearstrength was calculated by dividing the maximum breaking force by thearea of the bonded specimen.

EXAMPLE 19 Inventive Glass-Ionomer Bone Cement Based on Photo InitiationSystems

The specimens made in Example 18b were evaluated using the methodsdescribed in Example 18c and results are shown in Table 4, and in FIGS.2 and 3. In Table 4, XM1, XM14, XM15 and XM16 were the cements with thesame copolymer (i.e., AA-IA-MGA) but with different liquid formulationsand different comonomers, whereas Vitremer was the commerciallyavailable light-cured glass-ionomer cement. The Vitremer glass was usedto formulate the inventive glass-ionomer cements. The cements wereconditioned in distilled water at 37° C. for 1 week. TABLE 4 MechanicalStrengths of Visible Light Initiated Hybrid Amino Acid ModifiedGlass-Ionomer Cements* Liquid FS CS DTS BM Formulation [MPa] [MPa] [MPa][GPa] Toughness Material (wt) (S.D.) (S.D.) (S.D.) (S.D.) (N · mm)Comonomer XM1 55:15:30 92.1 (10.4) 201.9 (9.16) 34.91 (4.48) 1.19 (0.02)15.9 (2.04) HEMA XM14 45:20:35 86.6 (2.77) 238.9 (21.4) 39.40 (6.01)1.45 (0.03) 13.4 (0.59) ABA XM15 40:30:30 76.3 (8.20) 265.1 (20.5) 36.38(3.48) 1.27 (0.32) 12.4 (1.23) AGA XM16 55:15:30 82.8 (4.86) 259.0(12.4) 41.10 (5.19) 1.57 (0.06) 13.1 (0.61) AGA Vitremer — 87.9 (1.35)172.7 (8.40) 31.30 (2.94) 1.19 (0.04) 15.0 (0.16) —*Liquid formulation was composed of IEM graftedterpolymer/comonomer/water; Grafting ratio = 25% (mole %); BM = bendingmodulus; Toughness = area under the load-displacement curve.Results in Table 4 showed that all the glass-ionomer cements of thepresent invention were comparable to commercial light-curable product,Vitremer, in most mechanical properties, but significantly higher in CS,DTS, and BM.

EXAMPLE 20 Inventive Glass-Ionomer Cement Based on Photo InitiationSystems

The specimens made in Example 18b were evaluated using the methodsdescribed in Example 18c. The results are shown in FIGS. 6, 7, 8 and 9.The copolymer used was the same as in Example 19. The commerciallyavailable GC Fuji II LC glass was used to formulate the inventiveglass-ionomer cements.

The cements were conditioned in distilled water at 37° C. for 1 week.FIG. 6 shows the compressive strength of the cements and viscosities ofthe polymer liquids composed of six amino acid derivatives, HEMA and AA.The liquid formulation was 50/25/25 based on polymer/comonomer/water andthe P/L ratio was 2.7/1. Among them, AA had the highest compressivestrength followed by AASPA, MBA, MGA, ABA, GA, ASPA and HEMA. Theviscosity (×10⁻³ cp) of the liquid was in the decreasing order:MASPA>AASPA>MGA>AGA>ABA>MBA>HEMA>AA. Considering strength and workingproperty of the cement, the MBA-containing cement had the lowestviscosity and highest compressive strength. FIG. 7 shows the effect ofliquid formulation on CS and viscosity. Both compressive strength andviscosity increased with increasing polymer content. The greater thepolymer content in the formulation, the higher were the mechanicalstrengths. As shown in FIG. 8, the compressive strength of the cementincreased with an increase of P/L ratio. However, when the ratio reached2.7/1, the CS did not increase but instead reached a plateau. FIG. 9shows the difference between the MBA-modified cement and GC Fuji II LCcement. The MBA modified cement exhibited significantly higher CS (259MPa), DTS (26.7 MPa) and FS (71.7 MPa), compared to corresponding 216,16 and 37 MPa for GC Fuji II LC cement.

EXAMPLE 21 Shear Bond Strength of Inventive Glass-Ionomer Cement Graftedwith Pendent IEM

The specimens made in Example 18b were evaluated using the methodsdescribed in Example 18d. The results are shown in Table 5. In Table 5,A2, B2 and C2 were the cements containing the same terpolymers but withdifferent amounts of polyacrylic acid. The copolymer was used as thesame as in Example 19. The commercially available GC Fuji II LC glasswas used to formulate the inventive glass-ionomer cements. Polyacrylicacid was also used in some of the formulations. Surface treatment of thedentin was divided into etching and non-etching as described in Example18d. The cements were conditioned in distilled water at 37° C. for 1week. TABLE 5 Shear Bond Strength (SBS) of Hybrid Amino Acid ModifiedGlass-Ionomer Cements Grafted with IEM, formulating with an Amino AcidComonomer and polyacrylic acid SBS [MPa] SBS [MPa] Non- Polyacrylic acidMaterial Ethed(S.D.) etched(S.D.) added (wt %) A2 11.4(0.41) 19.5(4.8) 0B2 11.1(5.42) 15.1(4.1) 6 C2 7.41(2.68) 19.9(4.2) 13  Fuji II LC12.0(4.07) N/A N/A*Grafting ratio = 25%; P/L ratio = 2/1; Liquid formulation = 50:20:30;ABA was used as comonomer; Cements were light-cured and were conditionedin distilled for 7 days before testing.

EXAMPLE 22 Inventive Glass-Ionomer Bone Cement Based on Redox InitiationSystems

The polymers synthesized in Example 12 and specimens made in Examples18a and b were evaluated using the methods described in Example 18c andresults are shown in Tables 6, 7 and 8, and FIG. 4. In Table 6, A1, B1and C1 were the cements with different liquid formulations; In Table 7,D1 to G1 were the cements with different grafting ratios. In Table 8, L1to O1 were the cements with different P/L ratios. Fuji II was thecommercially available glass-ionomer cement. The Fuji II LC glass wasused to formulate the inventive glass-ionomer cements. The cements wereconditioned in distilled water at 37° C. for 1 week. TABLE 6 MechanicalStrengths of Redox Initiated Hybrid Amino Acid Modified Glass-IonomerCements - Effect of Components in Liquid Formulation on Properties*Liquid CS [Mpa] Material Formulation (wt) (S.D) DTS [Mpa] (S.D) CT (min)A1 40/30/30 182.7 (7.72) 26.5 (2.98) 1.92 B1 50/18/32 192.2 (8.07) 28.6(3.11) 2.08 C1 60/15/25 185.0 (23.8) 27.5 (4.18) 3.22 Fuji II — 185.8(47.9) 18.0 (0.30) —*Grafting ratio = 15%; P/L ratio = 2/1; Amount of activator (ascorbicacid) = 0.3%; ABA was used as comonomer; CT = curing time.

TABLE 7 Effect of IEM Grafting Ratio on Polymer on Properties* GraftingRatio Liquid DTS (molar Formulation CS [Mpa] [Mpa] CT Material ratio)(wt) (S.D) (S.D) (min) D1 15% 40/30/30 182.7 (7.72) 26.5 (2.98) 1.92 E130% 40/30/30 173.8 (3.24) 29.6 (4.46) 2.13 F1 15% 60/15/25 185.0 (23.8)27.5 (4.18) 3.22 G1 30% 60/15/25 227.1 (10.4) 25.4 (4.98) 3.42 *P/Lratio = 2/1; Amount of activator = 0.3%. P/L Ratio Material (wt) CS(MPa) (S.D) DTS (MPa) (S.D) CT (min) L1 1.5/1 162.9 (10.3) 26.9 (2.77)2.32 M1 2.0/1 192.2 (8.07) 28.6 (3.11) 2.70 N1 2.5/1 212.5 (8.41) 30.5(5.25) 2.05 O1 3.0/1 232.7 (13.7) 31.0 (5.67) 1.75 *Grafting ratio =15%; Amount of activator = 0.3%; Ratio for liquid formulation =50/18/32.

Mechanical strengths of redox-initiated glass-ionomer cements of thepresent invention and the effects of grafting ratios and P/L ratios aredescribed in Tables 6, 7 and 8. The redox system exhibited improved DTSand comparable CS, compared to the Fuji II control, as shown in Table 6.Different grafting seems not to have much effect on mechanical strengthsof the cements. The higher the P/L ration, the higher the CS and DTS, asshown in Table 8.

EXAMPLE 23 Inventive Glass-Ionomer Bone Cement Grafted with Pendent GM

The polymers synthesized in Example 13 and specimens made followingExample 18 were evaluated using the methods described in Example 18c andresults are shown in Table 9 and FIG. 5. In Table 9, A, B, D, E and Hwere the cements with different liquid formulations initiated withvisible light, whereas F was the cement initiated using redox system.The Fuji II LC glass was used to formulate the inventive glass-ionomercements. The cements were conditioned in distilled water at 37° C. for 1week. TABLE 9 Mechanical Strengths of Hybrid Amino Acid ModifiedGlass-Ionomer Cements Grafted with Glycidyl Methacrylate* and containingan Amino Acid Comonomer Liquid FS DTS Formulation P/L Grafting [MPa] CS[MPa] [MPa] Material (wt) Ratio Ratio (S.D.) (S.D.) (S.D.) Initiation A50:20:30 2.7 15% 68.1 (8.5) 199.3 (7.9)  34.1 (1.8) LC B 60:15:25 2.715% 83.2 (3.8) 199.6 (3.7)  30.4 (1.8) LC D 50:20:30 2.0 15% 69.2 (2.4)174.8 (12.6) 32.9 (2.3) LC E 50:20:30 3.5 15% 65.7 (3.5) 208.5 (6.3) 37.1 (2.2) LC F 50:20:30 2.7 15% 64.0 (4.5) 221.3 (12.5) 35.1 (4.3)Redox H 50:20:30 2.7 30%  80.0 (11.9) 207.8 (10.3) 37.3 (2.2) LC Fuji II— — 18.0 (0.3) 189.5 (19.4) 21.6 (3.2) —*In liquid formulation, poly(acrylic acid-co-itaconic acid) copolymerwas used instead of poly(acrylic acid-co-itaconic acid-co-methacryloylglutamic acid) terpolymer; Glycidyl methacrylate was used as a graftingagent; The specimens were conditioned for 1 week prior to testing; LCstands for photo-initiation, whereas redox represents redox initiation.

As shown in Table 9, all glycidyl methacrylate grafted polycarboxylicacid-containing glass ionomers exhibited much higher values in FS (64.0to 83.2 Mpa), CS (174.8 to 221.3 Mpa) and DTS (30.4 to 37.3 Mpa)compared to Fuji II control (18.0 in FS, 189.5 in CS and 21.6 in DTS),even though there was no amino acid incorporated into the polymerbackbone.

CITATIONS OF PUBLICATIONS REFERENCED IN THE BACKGROUND SECTION

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All patent and non-patent publications cited in this specification areindicative of the level of skill of those skilled in the art to whichthis invention pertains. All these publications and patent applicationsare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated as being incorporated by reference herein.

Although the invention herein has been described with reference toparticular embodiments, it is to be understood that these embodimentsare merely illustrative of the principles and applications of thepresent invention. It is therefore to be understood that numerousmodifications may be made to the illustrative embodiments and that otherarrangements may be devised without departing from the spirit and scopeof the present invention as defined by the appended claims.

1. A composition for making an ionomeric cement, comprising at least onecopolymer comprising at least two different carboxylic acid-containingmonomers, wherein said copolymer has added thereon a bifunctionalmonomer having pendent polymerizable functional groups, and a comonomercontaining one or more polymerizable functional groups reactive withsaid polymerizable functional groups on said bifunctional monomer,wherein said comonomer, at least one of said carboxylic acid containingmonomers, or both, comprises an amino acid.
 2. The composition of claim1 wherein one of said carboxylic acid-containing monomers comprisesacrylic acid (AA).
 3. The composition of claim 1 wherein one of saidcarboxylic acid-containing monomers comprises itaconic acid (IA).
 4. Thecomposition of claim 1 wherein said two monomers comprise acrylic acidand itaconic acid.
 5. The composition of claim 1 wherein said copolymercomprises three different carboxylic acid-containing monomers, one ofwhich comprises an amino acid.
 6. The composition of claim 5 whereinsaid amino acid is an acryloyl amino acid or a methacryloyl amino acid.7. The composition of claim 6 wherein said amino acid is acryloyl aminoacid selected from the group consisting of acryloyl beta-alanine (ABA),acryloyl aspartic acid (AASPS), acryloyl glycine (AG), acryloyl glutamicacid (AGA), and acryloyl 6-aminocaproic acid (A6ACA).
 8. The compositionof claim 6 wherein said amino acid is a methacryloyl amino acid selectedfrom the group consisting of methacryloyl beta-alanine (MBA),methacryloyl glycine (MG), methacryloyl aspartic acid (MASPA),methacryloyl 6-aminocaproic acid (M6ACA) and methacryloyl methionine(MMET).
 9. The composition of claim 1 wherein said copolymer comprisesPoly(AA-IA-AGA) or Poly(AA-IA-MGA).
 10. The composition of claim 1wherein said copolymer comprises Poly(AA-IA-AG) or Poly(AA-IA-MG). 11.The composition of claim 1 wherein said copolymer comprisesPoly(AA-IA-ABA) or Poly(AA-IA-MBA).
 12. The composition of claim 1 saidcopolymer comprises Poly(AA-IA-A6ACA) or Poly(AA-IA-M6ACA).
 13. Thecomposition of claim 1 wherein said pendent polymerizable functionalgroups on said bifunctional monomer comprise ethylenically unsaturatedgroups.
 14. The composition of claim 13 wherein said bifunctionalmonomer is glycidyl methacrylate (GM) which is grafted onto saidcopolymer.
 15. The composition of claims 13 wherein said bifunctionalmonomer is 2-isocyanatoethylmethacrylate (IEM) which is grafted ontosaid copolymer.
 16. The composition of claim 1 wherein said pendentpolymerizable functional groups on said bifunctional monomer compriseepoxy groups.
 17. The composition of claim 1 wherein said comonomercomprises an acryloyl amino acid or a methacryloyl amino acid.
 18. Thecomposition of claim 1 wherein said comonomer comprises acryloylbeta-alanine.
 19. The composition of claim 1 wherein said comonomercomprises 2-hydroxyethyl methacrylate (HEMA).
 20. The composition ofclaim 1 wherein both one of said carboxylic-acid containing monomers andsaid co-monomer comprise an amino acid.
 21. The composition of claim 1comprising first and second copolymers, each of which contains an aminoacid-containing monomer, wherein the amino acid in each of saidcopolymers is different.
 22. The composition of claim 21 whereincombinations of said first and second copolymers arePoly(AA-IA-MGA)/Poly(AA-IA-M6ACA), Poly(AA-IA-MGA)/Poly(AA-IA-MG) orPoly(AA-IA-AASPA)/Poly(AA-IA-MG).
 23. The composition of claim 1 furthercomprising polyacrylic acid.
 24. An ionomeric cement comprising thecomposition of claim 1, a reactive filler and water.
 25. The cement ofclaim 24 further comprising a polymerization initiator.
 26. The cementof claim 25 wherein said initiator comprises a photo-initiator.
 27. Thecement of claim 25 wherein said initiator comprises a reducing agent andan oxidizing agent.
 28. The cement of claim 27 wherein said reducingagent comprises ascorbic acid.
 29. The cement of claim 27 wherein saidreducing agent is in encapsulated form.
 30. The cement of claim 24further comprising a polymerization inhibitor.
 31. The cement of claim30 wherein said inhibitor is butylated hydroxytoluene.
 32. The cement ofclaim 24 further comprising a modifying agent.
 33. The cement of claim32 wherein said modifying agent comprises tartaric acid.
 34. The cementof claim 24 further comprising polyacrylic acid.
 35. A kit for preparingan ionomeric cement composition, comprising: a first package containingat least one copolymer comprising at least two different carboxylicacid-containing monomers, wherein said copolymer has added thereon abifunctional monomer having pendent polymerizable functional groups, anda comonomer containing one or more polymerizable functional groups andthat is reactive with said polymerizable functional group on saidbifunctional monomer, wherein said comonomer, at least one of saidcarboxylic acid-containing monomers, or both, comprises an amino acid.36. The kit of claim 35 wherein said first package further compriseswater, and wherein said kit further comprises a second packagecomprising a reactive filler.
 37. The kit of claim 36 wherein saidsecond package further comprises a reducing agent.
 38. The kit of claim35 wherein said first package further comprises a reactive filler andwherein said kit further comprises a second package comprising water.39. The kit of claim 35 wherein said copolymer and said comonomer arepresent in lyophilized form.
 40. The kit of claim 35 further comprisinga second package and wherein one of said packages further comprises areducing agent and the other of said packages further comprises anoxidizing agent.
 41. A polymerization system comprising at least onecopolymer comprising at least two different carboxylic acid-containingmonomers, one of said monomers being an amino acid, wherein saidcopolymer has added thereon a bifunctional monomer having pendentpolymerizable functional groups, and a comonomer containing one or morefunctional groups reactive with said polymerizable functional groups onsaid bifunctional monomer.
 42. A polymerization system comprising atleast one copolymer comprising at least two different carboxylicacid-containing monomers, wherein said copolymer has added thereon abifunctional monomer having pendent polymerizable functional groups, andan amino acid comonomer having polymerizable functional groups reactivewith said polymerizable functional groups on said bifunctional monomer.43. The composition of claim 1, wherein said copolymer comprises saidcomonomer.